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Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Hippo pathway activation causes multiple lipid derangements in a murine model of cardiomyopathy
Wei Wu1, Kevin Huynh2, Jin-Chan Du3
1Department of Cardiology, Shaanxi Provincial Hospital, Xi'an, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Insights
Cardiac Hippo pathway activation alters lipid profiles in cardiomyopathy by reducing beneficial lipids and increasing harmful ones, driven by suppressed PPARα/PGC-1α signaling.
Area of Science:
- Cardiovascular Biology
- Metabolic Pathways
- Molecular Cardiology
Background:
- Metabolic reprogramming is a hallmark of cardiomyopathy and heart failure, contributing to disease progression.
- Cardiac Hippo pathway activation is linked to mitochondrial dysfunction and metabolic changes, but its role in lipid profiles remains unclear.
Purpose of the Study:
- To investigate the impact of enhanced cardiac Hippo pathway signaling on cardiac lipid profiles in a mouse model of cardiomyopathy.
- To elucidate the molecular mechanisms underlying these lipid alterations.
Main Methods:
- Utilized a dual-omics approach combining lipidomics and transcriptomics in a mouse model of cardiomyopathy with enhanced Hippo signaling.
- Performed lipidomic profiling to identify changes in various lipid classes.
- Conducted transcriptomic analysis to explore molecular mechanisms, focusing on PPARα/PGC-1α signaling and related gene sets.
Main Results:
- Lipidomic profiling revealed significant alterations, including reduced triacylglycerol, diacylglycerol, phospholipids, and ether lipids, alongside elevated sphingolipids and lysophosphatidylcholine.
- Mechanistically, downregulated expression of PPARα (peroxisome proliferator-activated receptor alpha) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and their target genes indicated attenuated transcriptional activity.
- Lipidomics-guided transcriptomics showed dysregulated gene sets involved in ceramide biosynthesis, suppressed triglyceride metabolism, and reduced mitochondrial fatty acid oxidation and ether lipid biosynthesis.
Conclusions:
- Activation of the cardiac Hippo pathway in cardiomyopathy leads to significant alterations in cardiac lipid profiles.
- Attenuated PPARα/PGC-1α signaling is a key mechanism driving these lipidomic changes in the failing heart.
- These findings highlight the Hippo pathway's role in metabolic dysregulation in cardiomyopathy, impacting lipid metabolism.
Abstract:
Metabolic reprogramming occurs in cardiomyopathy and heart failure contributing to progression of the disease. Activation of cardiac Hippo pathway signaling has been implicated in mediating mitochondrial dysfunction and metabolic reprogramming in cardiomyopathy, albeit influence of Hippo pathway on lipid profile is unclear. Using a dual-omics approach, we determined alterations of cardiac lipids in a mouse model of cardiomyopathy due to enhanced Hippo signaling and explored molecular mechanisms. Lipidomic profiling discovered multiple alterations in lipid classes, notably reduction of triacylglycerol, diacylglycerol, phospholipids and ether lipids, and elevation of sphingolipids and lysophosphatidylcholine. Mechanistically, we found downregulated expression of PPARα and PGC-1α at mRNA and protein levels, and downregulated expression of PPARα-target genes, indicating attenuated transcriptional activity of PPARα/PGC-1α. Lipidomics-guided transcriptomic analysis revealed dysregulated expression of gene sets that were responsible for enhanced biosynthesis of ceramides, suppression of TG biosynthesis, storage, hydrolysis and mitochondrial fatty acid oxidation, and reduction of peroxisome-localized biosynthesis of ether lipids. Collectively, Hippo pathway activation with attenuated PPARα/PGC-1α signaling is the underlying mechanism for alterations in cardiac lipids in cardiomyopathy and failing heart.
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